Diffuse Optical Tomography (DOT) is a technique wherein tissue is illuminated at multiple source points on a tissue surface with electromagnetic energy having wavelengths ranging from visible light to near infrared (NIR). Light transmitted through the tissue from each source point is then detected at each of multiple reception points on the tissue surface to measure attenuation and scattering along paths from each source point to each reception point. Scattering is mainly the result of light interactions with solid or semi-solid masses, whereas attenuation of the radiation over the pathlength may be caused by absorption and/or emission. For example, light is absorbed by compounds (chromophores) within the tissue, such as hemoglobin, myoglobin, lipids and water, that interact with electromagnetic energy of a particular wavelength. Emission—radiation of energy from a molecule—can result from naturally occurring fluorescent and bioluminescent molecules and/or from medical imaging compositions in the tissue.
Measuring and modeling of attenuation and scattering allows for the creation of potentially high contrast images. For example, the heme group of myoglobin and/or hemoglobin absorbs visible and near infrared radiation, and the spectral characteristics of the absorption vary noticeably with the degree of oxygenation. Therefore, high contrast may be obtained between portions of the tissue containing high concentrations of heme (such as blood and muscle) and portions of tissue containing low concentrations of heme (such as fat), and between highly oxygenated and poorly oxygenated or infarcted tissues. In particular, the high vascularity in tumors provides an elevated hemoglobin content and a potentially high intrinsic optical contrast between the tumor and normal tissue.
Modeling of the tissue is typically performed with a computerized tissue model having parameters that are adjusted such that modeled tissue matches the measured attenuation and scattering along each path. In some models, chromophore concentrations and scatter parameters are determined by comparing absolute transmission data to known (signature) spectra. Such systems are subject to large noise contributions and errors, such as variations between source and detector coupling coefficients, boundary reflection mismatches, and inaccurate geometric modeling. These errors arise because the systems attempt to match model-calculated data with calibrated measurement data, which often contains these coupling/boundary errors.
Spectrally-constrained models, such as Direct Chromophore Spectral Reconstruction (DCSR), show improved accuracy and are more robust in the presence of noise than conventional models, because they use coupled spectral information to constrain the reconstruction. DCSR is, however, subject to some of the same measurement errors as traditional methods, namely, coupling coefficient and external boundary variations, as well as inaccurate geometric modeling. See, for example, Srinivasan, S.; Pogue, B. W.; Jiang, S.; Dehghani, H.; Paulsen, K. D. “Spectrally Constrained Chromophore and Scattering NIR Tomography Provides Quantitative and Robust Reconstruction”, Applied Optics, 44(10), 1858-1869, (2004) and Corlu, A.; Durduran, T.; Choe, R.; Schweiger, M.; Hillman, E. M. C.; Arridge, S. R.; Yodh, A. G. “Uniqueness and Wavelength Optimization in Continuous-Wave Multispectral Diffuse Optical Tomography”, Optics Letters, 28(23), 2339-2341, (2003). The parameterized tissue model is projected onto one or more hypothetical image planes, which are prepared as two-dimensional cross-sectional slices and/or three-dimensional images.
Systems for optical tomography, similar to that described in C. H. Schmitz, M. Löcker, J. M. Lasker, A. H. Hielscher, and R. L. Barbour, “Instrumentation for fast functional optical tomography,” Rev. Sci. Instr., 73(2): 429-439 (2002), have been marketed by NIRx Medical Technologies, LLC of Glen Head, N.Y. The system marketed by NIRx can resolve 5-millimeter lesions 3 centimeters below the skin surface. The system of Schmitz mechanically distributes light from a single laser into multiple illumination points spaced over the tissue to be studied in succession. As each illumination point is illuminated, light received at multiple reception points spaced over the tissue is measured. With the apparatus of Schmitz, data for approximately 3 image planes per second can be acquired.
The amount of heme at a particular soft-tissue location can, however, vary rapidly, so that acquisition of data at a rate of 3 image planes per second may be insufficient to accurately detect a physiological occurrence or anomaly. For example, both elastic and muscular arteries, including associated pathology such as aneurysms, may enlarge and shrink with each heartbeat. Active muscle and brain tissue not only is known to consume oxygen at an activity-dependent rate, thereby changing its spectral characteristics, but it releases local vasoactive substances such as adenosine with resulting activity-dependent vasodilation occurring in seconds. Vasculature in different tissue types, such as tumor and surrounding tissue, can also respond differently to exogenous vasoactive substances. Similarly, since the corpora cavernosa may undergo rapid changes in heme content and oxygenation, imaging of those changes could be of interest in the study, diagnosis and treatment of erectile dysfunction or priapism.
The degree of oxygenation and heme content of soft tissue regions under varying conditions can be of interest to a physician attempting to diagnose disease. For example, it is known that many malignant tumors require so much oxygen that portions of the tumor may become ischemic and necrotic despite their increased vascularity. Much heart disease is ischemic, as are many strokes. Peripheral vascular disease, often implicated in diabetic foot ulcers, often produces—sometimes activity-dependent—inadequate blood flow and abnormal zones of ischemia in peripheral tissue such as limb tissue. These zones of ischemia tend to be more prone to forming slow or non-healing ulcers than normally oxygenated tissue. Accurate imaging of vessel obstructions and ischemia in tissue may allow for more successful debridement of ulcers and permit success with other treatments such as revascularization. Imaging of rapid activity-dependent changes in regional distribution of heme content and oxygenation of brain tissue could be of interest in research into brain function, as well as in the diagnosis of a wide variety of neurological conditions including epilepsy.
It is desirable to have a short acquisition time to measure the dynamic aspects of heme distribution, also known as hemodynamics. It has been proposed that scattering and attenuation for multiple paths can be acquired simultaneously using intensity modulation encoding of the source. Franceschini (Francheschini et al, “Frequency-domain techniques enhance optical mammography: Initial clinical results” Proc Natl Acad Sci USA. 94(12): 6468-6473, 1997) demonstrated this approach with a frequency domain source, and the concept was further developed by Siegel (Siegel, A M, Marota, J J A and Boas, D A. “Design and evaluation of a continuous-wave diffuse optical tomography system.” Optics Express 4:287-298, 1999) for a continuous wave source based system. Siegel developed a system where several source points are illuminated at the same time. Light applied to each simultaneously-illuminated source point is amplitude modulated such that light from that source point can be distinguished from light applied to other simultaneously-illuminated source points, by having a different modulation frequency. For example, if one source point is amplitude-modulated with a first tone, and a second source point is amplitude-modulated with a second tone, light received at a reception point can be distinguished by measuring a ratio between the first and second tone in modulation as received at the reception point.